1. Field of the Invention
This Application is a .sctn.371 of PCT/US92/09560, filed on Nov. 17, 1992.
The present invention relates to cyclic phenolic thioethers. More particularly, the present invention relates to the novel compounds of Formula I, which are inhibitors or stimulators of superoxide generation, and which may also inhibit cyclooxygenase and/or 5-lipoxygenase, to pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and to medical methods of treatment employing these compounds.
The compounds of the present invention which stimulate superoxide generation may be useful as adjunctive therapeutic agents in the treatment of infections. Other compounds of the present invention which inhibit superoxide generation may be useful in the therapeutic or prophylactic treatment of disease conditions which are mediated wholly or partly by superoxide generation, such as adult respiratory distress syndrome, superoxide mediated inflammatory or allergic conditions, and other medical conditions which are caused by or aggravated by superoxide.
The compounds of Formula I which inhibit cyclooxygenase or 5-lipoxygenase are useful, for example, as anti-inflammatory and/or anti-allergy agents and in the treatment of hypersensitivity reactions, psoriasis, asthma, and related disorders and conditions in which physiologically active agents formed in the arachidonic acid metabolic pathway are involved. Compounds of the present invention may be useful in treating inflammatory and allergic conditions such as arthritis, asthma, and psoriasis.
2. Background Information
Recently, oxygen radicals have been implicated in the pathogenesis of many diseases. This implication is reflected by the many conferences devoted to this topic, books on the subject of free radicals and disease, and the appearance of two new specialized journals: Free Radical Research Communications, and Free Radical Biology and Medicine.
Much is known about the physicochemical properties of the various oxygen radicals, but knowledge of their overall importance in the initiation and amplification of human disease is limited. Some clinical conditions in which oxygen radicals are thought to be involved are discussed in Cross, C. E., et al., "Oxygen Radicals and Human Disease," ANN. INT. MED., 107:526-545 (1987) (see Table 1, p. 527) and Ward, P. A., et al., "Oxygen Radicals, Inflammation, and Tissue Injury," FREE RADICAL BIOLOGY & MEDICINE, 5:403-408 (1988), each of which is incorporated herein by reference. Among the clinical conditions in which oxygen radicals are thought to be involved are, for example, inflammatory-immune injury, autoimmune diseases, ischemia-reflow states, aging disorders, cancer, cigarette-smoke effects, emphysema, acute respiratory distress syndrome (ARDS), atherosclerosis, rheumatoid arthritis, senile dementia, cataractogenesis, retinopathy of prematurity, radiation injury and contact dermatitis.
Oxygen radicals are capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, protein and free amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These species may have an impact on such cell activities as membrane function, metabolism, and gene expression. Oxygen radicals are formed in tissues by many processes (see Cross, et al., p. 528, Table 2). These are believed to be both endogenous, such as mitochondrial, microsomal and chloroplast electron transport chains; oxidant enzymes such as xanthine oxidase, indoleamine dioxygenase, tryptophan dioxygenase, galactose oxidase, cyclooxygenase, lipoxygenase, and monoamine oxidase; phagocytic cells, such as neutrophils, monocytes and macrophages, eosinophils, and endothelial cells; and antioxidation reactions; and exogenous, such as redoxcycling substances, drug oxidations, cigarette smoke, ionizing radiation, sunlight, heat shock and substances that oxidize glutathione. They may be involved in the action of toxins such as paraquat, cigarette smoke, and quinone antitumor drugs.
Those compounds of the present invention which inhibit superoxide generation may be useful in the treatment of diseases mediated by superoxide generation.
There are also some conditions in which the generation of superoxide may be desirable. Those compounds of the present invention which stimulate superoxide generation may be useful in the adjunctive therapy of microbial infections. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics (7th Edition, 1985) p. 660-673; P. A. Ward, et. al., "Oxygen Radicals, Inflammation and Tissue Injury," FREE RADICAL BIOLOGY & MEDICINE, 5:403-408 (1988); and C. E. Cross, et. al., "Oxygen Radicals and Human Disease,"; ANN. INT. MED., 107: 526-545 (1987), each of which is incorporated herein by reference. Generation of reactive oxygen species is a critical event in successful host defense against invading organisms. Both neutrophils and macrophages rely on a variety of oxidants to damage bacterial constituents (see V. L. Shepherd, "The role of the respiratory burst of phagocytes in host defense," SEMIN RESPIR. INFECT. (United States) June 1986, 1(2) p. 99-106, which is incorporated herein by reference.
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects.
Those compounds of the present invention which inhibit cyclooxygenase inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin synthetase inhibitors may exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are useful in the treatment of inflammatory conditions such as arthritis.
The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions, inflammation and other allergic responses.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as A.sub.4, B.sub.4, C.sub.4, D.sub.4, and E.sub.4. LTC.sub.4 is at least 100 times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction. LTB.sub.4 may be an important mediator of inflammation in, for example, inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB.sub.4 is not only chemotactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB.sub.4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB.sub.4 may, thus, play an important role in mediating both acute and chronic inflammation.
Rheumatoid spondylitis is characterized by an acute neutrophil flareup in the joint which is associated with elevated levels of LTB.sub.4. LTB.sub.4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB.sub.4 production by neutrophils. Accordingly, those compounds of the present invention which inhibit 5-lipoxygenase through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
Prior to the recognition of the significance of the arachidonic acid metabolism pathway in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation. There has since been an effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides new chemical entities which are inhibitors of the arachidonic acid pathway and are useful in the treatment of asthma, rheumatoid arthritis, osteoarthritis, psoriasis, and other allergic, hypersensitivity, and inflammatory conditions. Further examples of inflammatory conditions or diseases with an inflammatory or immune system component are disclosed in, for example, the Merck Manual of Diagnosis and Therapy, 15th Edition (1987) which is incorporated herein by reference.
Various thioether compounds have been described previously. For example, U.S. Pat. No. 4,711,903 and its continuation-in-part, U.S. Pat. No. 4,755,524, disclose compounds of the formula: ##STR2## wherein: R.sub.1 and R.sub.2 are the same or different and independently represent tert-alkyl or phenyl; A represents methylene or methylene substituted by alkyl, dialkyl or hydroxy, provided that when A includes hydroxymethylene, the hydroxymethylene group is not adjacent to a heteroatom; B represents sulfur, sulfoxide, sulfone, oxygen, --NH-- or nitrogen substituted by alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; C represents methylene or methylene substituted by alkyl; R.sub.3 represents CO.sub.2 H, CO.sub.2 -alkyl or a tetrazole group; m is 0 or 1, n is 2, 3 or 4 and p is 1, 2 or 3; and the pharmaceutically acceptable salts thereof. The compounds are specific inhibitors of 5-lipoxygenase, and are useful in the treatment of local and systematic inflammation, allergy and hypersensitivity reactions and other disorders in which agents formed in the 5-lipoxygenase metabolic pathway are involved.
U.S. Pat. No. 4,621,098 and its equivalent, European Patent Application Publication No. 0131221, disclose compounds of the formula: ##STR3## in which Ar is phenyl or phenyl substituted by one to three of varied substituents, for example, alkyl, alkoxy, hydroxy, etc.; Q is oxygen, sulfur or an NH group; A is straight or branched chain, optionally substituted, alkylene, and R is hydrogen or straight or branched alkyl, optionally substituted by alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, etc.; and n is 0, 1 or 2. The disclosed compounds are indicated to have anti-inflammatory and anti-allergic properties through inhibition of undefined anaphylactic and anaphylactoid reactions, although no test data are provided. The preferred compounds are stated to be those in which Q represents oxygen and n is 0, without mention of any preference among the numerous possible substituents for R or substituted phenyl as Ar. In contrast to the invention disclosed in the foregoing publication, the compounds of the present invention all have cycloalkyl at the position corresponding to A as well as having di(tertiary)-alkyl or diphenyl groups as substituents on the phenol moiety corresponding to the substituted Ar group in the above publication which, as described therein, may or may not comprise a phenol.
U.S. Pat. Nos. 4,029,812, 4,076,841 and 4,078,084 disclose compounds of the formula: ##STR4## comprising 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)thio carboxamides. The compounds are indicated to be useful in lowering serum cholesterol and triglyceride levels.
A series of thioethers, useful as, for example, polyfunctional antioxidants for polymers, and biologically active substances, obtained by the nucleophilic addition of thiols, including 3,5-di-tert-butyl-4-hydroxythio-phenol, and hydrogen sulfide to acrylate derivatives have been described. See Medvedev et al., Khimiya; Khimicheskaya Tekhnologiya, Volume 20, (1977), pp. 568-574. The compounds resulting from the foregoing process have the general formulas RS(CH.sub.2).sub.n X and S(CH.sub.2 CH.sub.2 X).sub.2 in which R is 3,5-di-tert-butyl-4-hydroxyphenyl and X represents, for example, --C.tbd.N, NH.sub.2, CH(OH)CH.sub.2 Cl, OH, COCl and various carboxy, carboxylate and amide functions. Compounds of formula I according to the present invention, or 5-lipoxygenase activity for structurally related compounds, are not disclosed. U.S. Pat. No. 4,153,803 discloses cholesterol-lowering phenoxyalkanoic acid esters of the formula: ##STR5## wherein, when Y is sulfur, X is hydrogen, benzyl, benzyloxy or benzylthio or substituted derivatives thereof; R is hydrogen, halogen, hydroxy, alkyl or alkoxy, A.sup.1 and A.sup.2 are hydrogen or alkyl and Z is amine or azacyclohydrocarbonyloxy.
JP 49116035 discloses a process for making compounds of the formula: ##STR6## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen, alkyl or aryl groups, and R.sup.1 and R.sup.2 can be combined to form a cycloalkyl group. The compounds are said to be useful as drug intermediates, agricultural chemicals, antioxidants and industrial chemicals. Specifically disclosed is a compound of the formula: ##STR7##
CA 107:197783q discloses dialkylphenol derivatives of the formula: ##STR8## wherein R.sup.1, R.sup.2 =alkyl; A=alkylene, S, SO; Y=alkoxyimino, O; Z=alkylene, O; n=1, 2; 2-3 saturated or unsaturated. The compounds are said to be useful as modifiers for biosynthesis of prostaglandins and leukotrienes and hypolipemics (no data).
These compounds differ structurally from the compounds claimed in the present application which have a carboxylic acid or ester moiety attached to the cycloalkyl ring through A--(CH.sub.2).sub.p or through A--(CH.sub.2).sub.p --C(O)--(CH.sub.2).sub.t and which do not have an alkoxyimino or .dbd.O attached to the cycloalkyl ring.
EP0293900 discloses 5-lipoxygenase inhibiting compounds of the formula: ##STR9## where R.sup.3 and Y together are: ##STR10## and n is 2 or 3.
These compounds differ structurally from the claimed compounds. They have a lactone structure (i.e., a dihydro-furanone or dihydro-pyranone) attached to the phenylthio, and lack a carboxylic acid or ester moiety attached to the heterocyclic ring through A--(CH.sub.2).sub.p or through A--(CH.sub.2).sub.p --C(O)--(CH.sub.2).sub.t.
Katsumi, et al., CHEM. PHARM. BULL. 34(4):1619-1627(1986) discloses 3,5-di-tert-butyl-4-hydroxystyrenes. Some of the compounds disclosed had anti-inflammatory activity and some inhibited 5-lipoxygenase. Only one compound (Compound 3, Table I) had S attached to the 3,5-di-tert-butyl-4-hydroxyphenol. It has the following structure: ##STR11## This compound differs structurally from the claimed compounds. It has a butyrolactone (i.e., a dihydro-2(3H)-furanone) attached to the thio and lacks a carboxylic acid or ester moiety attached to the heterocyclic ring through A--(CH.sub.2).sub.p or through A--(CH.sub.2).sub.p --C(O)--(CH.sub.2).sub.t. At the bottom of page 1621, the authors indicate that insertion of the thio group resulted in a loss of anti-inflammatory activity.
U.S. Pat. No. 4,801,611 discloses 5-lipoxygenase inhibitors of the formula: ##STR12## where R.sub.1 and R.sub.2 are tert-alkyl and R.sub.3 can be: ##STR13## where R.sub.6 and R.sub.7 are C.sub.1-4 alkyl.
These compounds differ structurally from the compounds of the present invention. Compound (c) has a dialkyl-1,3-dioxanyl group attached to the phenylthio through an alkylene bridge whereas compound (d) has a 4-hydroxy-2-pyranone attached to the phenylthio through an alkylene bridge. Neither compound has a carboxylic acid or ester moiety attached to the cycloalkyl ring through A--(CH.sub.2).sub.p or through A--(CH.sub.2).sub.p --C(O)--(CH.sub.2).sub.t, as do the compounds of the present invention, and both compound have an alkylene bridge inserted between the phenylthio and the heterocyclic ring.
Each of the documents described hereinabove discloses compounds which are structurally different from the compounds of the present invention. Thus, the compounds of the present invention are structurally distinct from that which has been described in the art.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDS have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson, PROC. NATL. ACAD. SCI. USA, 89, 7384 (1992), which is incorporated herein by reference, and named cyclooxygenase II (COX II) or prostaglandin G. H. synthase II. The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer, et al, PROC. NATL. ACAD. SCI. USA, 89, 8917 (1992), which is incorporated herein by reference). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (J. BIOL. CHEM., 268, 6610 (1993), which is incorporated herein by reference). In addition, Futaki et al (GEN. PHARMAC., 24, 105 (1993), which is incorporated herein by reference,) has reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide is anti-inflammatory and lacks gastric side effects.
Compounds of the present invention inhibit cyclooxygenase II and/or cyclooxygenase I, and relieve the effects of inflammation. These compounds, in addition, produce a reduced amount of side effects.
Compounds of the present invention would be useful for the treatment of inflammation in an animal, and for treatment of other inflammation-associated disorders, such as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the present invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, systemic lupus erythematosus, osteoarthritis and juvenile arthritis. Such compounds would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of the present invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Compounds of the present invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet'3 s syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis, swelling occurring after injury, myocardial ischemia, and the like. Compounds of the present invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
The present invention also comprises a method of treating inflammation or inflammation-associated disorders in a subject, the method comprising administering to the subject having such inflammation or disorder a therapeutically-effective amount of a compound of Formula I.